Although no major causative genes have yet been identified there is strong evidence that the risk of glioma has a genetic predisposition. In 2007, we established the international Gliogene Consortium involving 14 centers in the US, Sweden, Denmark, Israel, and the UK to identify genetic determinants of familial glioma. We have shown evidence for genetic linkage of familial glioma to chromosomal region 17q12-q21.32. For this competing renewal we propose to collect 500 additional families to allow us to conduct our gene discovery effort stratifying by molecular subgroups, and to apply emerging genetic methodologies, including exomic sequencing, to identify the specific genes involved in risk of familial glioma syndrome(s). To accomplish our overarching goal of identifying glioma risk genes, we propose for Aim 1 to characterize a cohort of 1000 glioma families with 2 or more cases of histologically verified glioma. We will stratify by molecular subtype, clinical presentation including age of onset, number of affected family members (i.e. to estimate penetrance), and familial patterns of cancers at other organ sites to define new cancer syndromes. For Aim 2 we will perform array-based genotyping for linkage analysis on all informative glioma families to identify families linked to genetic loci, and to have sufficient power to stratify our linkage analysis by: a) age of onset;b) presumptive mode of inheritance, c) co-occurrence of cancers (glioma and melanoma, and pancreas), d) histology, and e) molecular subtype. Aim 3 is to perform high-throughput whole exome sequencing in familial glioma cases, prioritized by number of glioma cases in the family (3 or more), and available DNA from at least two family members to identify causative germ line mutations. We expect from these analyses we will have a >80% probability of detecting a disease-causing allele with frequencies of >0.005. In summary, this study capitalizes on the outstanding infrastructure, and builds upon a unique annotated data and specimen repository which is a resource for future studies. We will be able to conduct a detailed assessment of the relationships between genotypes, molecular subtype, and clinical pathological phenotypes, and quantification of mutation penetrance. In addition, the ultimate goal of this research is to develop information directly relevant for genetic counseling of individuals at risk of inherited glioma. PUBLIC HEALTH RELEVANCE: Glioma is a tumor with poor prognosis where it is critical to develop additional treatment and surveillance strategies. The goal of this international Consortium study is to identify susceptibility loci explaining familial glioma. With a large number of glioma families we will conduct our gene discovery effort stratifying by glioma molecular subgroups, and apply emerging genetic methodologies, including exomic sequencing, to identify the specific genes involved in risk of familial glioma syndrome(s).